Cerebral Amyloid Angiopathy-related Intracerebral Hemorrhage Research Articles

Serum YKL-40 as a Predictive Biomarker of Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage Recurrence.

Neuroinflammation is a major cause of secondary brain injury in intracerebral hemorrhage (ICH). To date, the prognostic value of YKL-40 (chitinase-3-like-1 protein), a biomarker of neuroinflammation, in cerebral amyloid angiopathy-related intracerebral hemorrhage (CAA-ICH) remains undiscovered. To evaluate the relationships between serum YKL-40 and CAA-ICH recurrence. Clinical and imaging information of 68 first-onset probable CAA-ICH cases and 95 controls were collected at baseline. Serum YKL-40 was measured by Luminex assay. Cox proportional hazards model was used to analyze the associations between YKL-40 level and CAA-ICH recurrence. Serum YKL-40 level was significantly higher in CAA-ICH cases than healthy controls (median [interquartile range, IQR], 46.1 [19.8, 93.4] versus 24.4 [13.9, 59.0] ng/mL, p = 0.004). Higher level of YKL-40 predicted increased risk of CAA-ICH recurrence adjusted for age, ICH volume and enlarged perivascular space score (ePVS) (above versus below 115.5 ng/ml, adjusted hazard ratios 4.721, 95% confidence intervals 1.829-12.189, p = 0.001) within a median follow-up period of 2.4 years. Adding YKL-40 to a model of only MRI imaging markers including ICH volume and ePVS score improved the discriminatory power (concordance index from 0.707 to 0.772, p = 0.001) and the reclassification power (net reclassification improvement 28.4%; integrated discrimination index 11.0%). Serum YKL-40 level might be a candidate prognostic biomarker for CAA-ICH recurrence.

Prevalence, Characteristics, and Outcomes of Undetermined Intracerebral Hemorrhage: A Systematic Review and Meta-Analysis.

There are scarce data regarding the prevalence, characteristics and outcomes of intracerebral hemorrhage (ICH) of undetermined (unknown or cryptogenic) etiology. We sought to determine the prevalence, radiological characteristics, and clinical outcomes of undetermined ICH. Systematic review and meta-analysis of studies involving patients with spontaneous ICH was conducted to primarily assess the prevalence and clinical-radiological characteristics of undetermined ICH. Additionally, we assessed the rates for ICH secondary to hypertensive arteriopathy and cerebral amyloid angiopathy. Subgroup analyses were performed based on the use of (1) etiology-oriented ICH classification, (2) detailed neuroimaging, and (3) Boston criteria among patients with cerebral amyloid angiopathy related ICH. We pooled the prevalence rates using random-effects models, and assessed the heterogeneity using Cochran Q and I2 statistics. We identified 24 studies comprising 15 828 spontaneous ICH patients (mean age, 64.8 years; men, 60.8%). The pooled prevalences of hypertensive arteriopathy ICH, undetermined ICH, and cerebral amyloid angiopathy ICH were 50% (95% CI, 43%–58%), 18% (95% CI, 13%–23%), and 12% (95% CI, 7%–17% [P<0.001 between subgroups]). The volume of ICH was the largest in cerebral amyloid angiopathy ICH (24.7 [95% CI, 19.7–29.8] mL), followed by hypertensive arteriopathy ICH (16.2 [95% CI, 10.9–21.5] mL) and undetermined ICH (15.4 [95% CI, 6.2–24.5] mL). Among patients with undetermined ICH, the rates of short-term mortality (within 3 months) and concomitant intraventricular hemorrhage were 33% (95% CI, 25%–42%) and 38% (95% CI, 28%–48%), respectively. Subgroup analysis demonstrated a higher rate of undetermined ICH among studies that did not use an etiology-oriented classification (22% [95% CI, 15%–29%]). No difference was observed between studies based on the completion of detailed neuroimaging to assess the rates of undetermined ICH (P=0.62). The etiology of spontaneous ICH remains unknown or cryptogenic among 1 in 7 patients in studies using etiology-oriented classification and among 1 in 4 patients in studies that avoid using etiology-oriented classification. The short-term mortality in undetermined ICH is high despite the relatively small ICH volume.

The Use of Serum Matrix Metalloproteinases in Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage and Cognitive Impairment.

Neuroimaging has played a primary role in predicting intracerebral hemorrhage (ICH) recurrence of cerebral amyloid angiopathy (CAA); however, the utilities of biomarkers in CAA-related ICH and cognitive impairment remain unexplored. To investigate the correlations of serum levels of matrix metalloproteinase-2 (MMP-2), MMP-3, and MMP-9 with CAA-related MRI markers, ICH recurrence, and cognitive status. 68 cases with first probable CAA-ICH and 69 controls were recruited. Clinical and imaging data were obtained at baseline and serum MMPs in the acute phase were measured by Luminex multiplex assays. Cognitive status was assessed with the Chinese version of Mini-Mental State Examination within 10-14 days after ICH onset. Serum MMP-2 level was significantly lower in CAA-ICH patients than controls while MMP-9 was significantly higher. In CAA-ICH patients, MMP-3 level was significantly associated with lobar cerebral microbleeds count after adjusting age, sex, and hypertension (adjusted coefficient 0.368, 95%CI 0.099-0.637, p = 0.008). During a median follow-up of 2.4 years, higher level of MMP-2 predicted lower CAA-ICH recurrence after adjusting age (adjusted HR 0.326, 95%CI 0.122-0.871, p = 0.025), ICH volume (adjusted HR 0.259, 95%CI 0.094-0.715, p = 0.009), total MRI burden of SVD score (adjusted HR 0.350, 95%CI 0.131-0.936, p = 0.037) respectively. Besides, higher level of MMP-2 was significantly associated with decreased risk of cognitive impairment independent of age and ICH volume (adjusted OR 0.054, 95%CI 0.005-0.570, p = 0.015). Serum MMP-2 in acute phase might be a promising biomarker to predict CAA-ICH recurrence and to evaluate the risk of cognitive impairment.

Neurofilament light chain predicts risk of recurrence in cerebral amyloid angiopathy-related intracerebral hemorrhage.

Predicting recurrent intracerebral hemorrhage (ICH) related to cerebral amyloid angiopathy (CAA) currently relies on brain images. We aimed to investigate whether blood neurodegenerative biomarkers predict disease severity and ICH recurrence in CAA. We recruited 68 first probable CAA-ICH cases from a Chinese prospective cohort, and 95 controls. We used the single-molecule array to measure acute phase blood amyloid-40, amyloid-42, total tau and neurofilament light chain (NfL). We used multivariable Cox regression models to assess the association between blood biomarkers and CAA-ICH recurrence, and used the concordance (c-) index to assess prediction models. Blood amyloid-42/40, total tau, and NfL levels changed in CAA-ICH cases than controls. During a median follow-up of 2.4 years, NfL was associated with CAA-ICH recurrence (adjusted hazard ratio 2.14, 95% CI 1.57-2.93) independent of MRI burden of small vessel disease (SVD). The performance of a model to predict CAA-ICH recurrence using MRI burden of SVD alone (c-index 0.77) increased with the addition of NfL (c-index 0.88, 95% CI 0.73-1.00, p=0.019). Further, NfL was associated with baseline ICH volume, NIHSS and 6-month mRS score. Blood NfL is associated with severity and prognosis of CAA-ICH and is a promising addition to MRI burden of SVD to predict CAA-ICH recurrence.

Cerebral amyloid angiopathy-related intracerebral hemorrhage: Feasibility and safety of bedside catheter hematoma evacuation with urokinase

ObjectiveCerebral amyloid angiopathy (CAA) is an important cause of intracerebral hemorrhage (ICH). However, data on surgical intervention in CAA-related ICH is very limited. In this retrospective study we assessed safety and efficacy of free-hand catheter aspiration followed by local thrombolysis in CAA-related large ICH. Patients and MethodsPatients with CAA-related lobar ICH>30 ml that were treated with this catheter technique were identified from our prospective database. The catheter was inserted at the bedside in the core of the hematoma and urokinase (5000IE) was administered every 6 h for a maximum of 4 days. Evolution of hematoma volume, perihemorrhagic edema (PHE) and midline-shift (MLS) as well as adverse events and functional outcome were analyzed. ResultsTwenty-one patients (median age 79 years) were treated between 2013-2018. Hematoma volume decreased from 70 ml at admission (IQR 49–98 ml) to 52 ml (IQR 35−76 ml, p < 0.001) immediately after catheter aspiration, and to 23.5 ml (IQR 17–47 ml, p < 0.001) at the end of urokinase treatment. At day 4, PHE volume (from 45 ml [IQR 33–71 ml] to 36 ml [IQR 22–50 ml]; p = 0.001) and MLS (from 5 mm [IQR 3.5–7 mm] to 1 mm [IQR 0.5–3 mm]; p < 0.001) were reduced significantly. No infection was observed, rebleeding after administration of 4 × 5000IE urokinase occurred in one patient (5 %). At discharge, modified Rankin Scale was 3 in 33 %, 4 in 24 %, and 5 in 43 % of patients, and had further improved after rehabilitation to an mRS of 2 in 10 %, 3 in 38 %, 4 in 19 %, and 5 in 33 % (median 9 weeks after ictus). There were no patient deaths during this time. ConclusionsBedside catheter hematoma evacuation in large CAA-related ICH seemed feasible and safe and could immediately decrease mass effect. Further studies assessing functional outcome are warranted.

Clinical Relevance of Cerebral Small Vessel Diseases.

Clinical Relevance of Cerebral Small Vessel Diseases.

Clinical characteristics, medical treatments and functional outcomes of cerebral amyloid angiopathy-related intracerebral hemorrhage in Mainland China: A prospective multicenter hospital-based study

Clinical characteristics, medical treatments and functional outcomes of cerebral amyloid angiopathy-related intracerebral hemorrhage in Mainland China: A prospective multicenter hospital-based study

Nationwide survey on cerebral amyloid angiopathy in Japan.

A nationwide survey was conducted to understand the epidemiology of cerebral amyloid angiopathy-related intracerebral hemorrhage (CAA-related ICH) and cerebral amyloid angiopathy-related inflammation/vasculitis (CAA-ri) in Japan. To estimate the total number and clinical features of patients with CAA-related ICH and CAA-ri between January 2012 and December 2014 and to analyze their clinical features, questionnaires were sent to randomly selected hospitals in Japan. In the first survey, 2348 of 4657 departments responded to the questionnaire (response rate 50.4%). The total numbers of reported patients with CAA-related ICH and CAA-ri were 1338 and 61, respectively, and their total numbers in Japan were estimated to be 5900 [95% confidence interval (CI) 4800-7100] and 170 (95% CI 110-220), respectively. The crude prevalence rates were 4.64 and 0.13 per 100000 population, respectively. The clinical information of 474 patients with CAA-related ICH obtained in the second survey was as follows: (i) the average age of onset was 78.4years; (ii) the prevalence increased with age; (iii) the disease was common in women; and (iv) hematoma most frequently occurred in the frontal lobe. Sixteen patients with CAA-ri for whom data were collected in the second survey had the following characteristics: (i) median age of onset was 75years; (ii) cognitive impairment and headache were the most frequent initial manifestations; and (iii) focal neurological signs, such as motor paresis and visual disturbance, were frequently observed during the clinical course. The numbers of patients with CAA-related ICH and CAA-ri in Japan were estimated.

Blood-Brain Barrier Dysfunction in Small Vessel Disease Related Intracerebral Hemorrhage.

Background and Purpose: Hypertensive vasculopathy and cerebral amyloid angiopathy are the two most common forms of cerebral small vessel disease. Both forms are associated with the development of primary intracerebral hemorrhage, but the pathophysiological mechanisms underlying spontaneous vessel rupture remain unknown. This work constitutes a systematic review on blood-brain barrier dysfunction in the etiology of spontaneous intracerebral hemorrhage due to cerebral small vessel disease.Methods: We searched Medline (1946–2018) and Embase (1974–2018) for animal and human studies reporting on blood-brain barrier dysfunction associated with intracerebral hemorrhage or cerebral microbleeds.Results: Of 26 eligible studies, 10 were animal studies and 16 were in humans. The authors found indications for blood-brain barrier dysfunction in all four animal studies addressing hypertensive vasculopathy-related intracerebral hemorrhage (n = 32 hypertensive animals included in all four studies combined), and in four of six studies on cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 47). Of the studies in humans, five of six studies in patients with cerebral amyloid angiopathy-related intracerebral hemorrhage (n = 117) and seven out of nine studies examining intracerebral hemorrhage with mixed or unspecified underlying etiology (n = 489) found indications for blood-brain barrier dysfunction. One post-mortem study in hypertensive vasculopathy-related intracerebral hemorrhage (n = 82) found no evidence for blood-brain barrier abnormalities.Conclusions: Signs of blood-brain barrier dysfunction were found in 20 out of 26 studies. Blood-brain barrier integrity deserves further investigation with a view to identification of potential treatment targets for spontaneous intracerebral hemorrhage.

Clinico-Radiological Characteristics and Pathological Diagnosis of Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage

We aim to clarify the clinico-radiological characteristics of cerebral amyloid angiopathy-related intracerebral hemorrhage and to investigate the efficacy of pathological diagnosis using biopsy specimens. We retrospectively reviewed 253 consecutive patients with cortico-subcortical hemorrhage who had been admitted to Aizawa Hospital between January 2006 and July 2013. We had performed craniotomy and hematoma evacuation in 48 patients, as well as biopsy of the evacuated hematoma, cerebral parenchyma adjacent to the hematoma, or both, and they were classified according to the histological results (positive or negative for vascular amyloid deposition) and to the Boston criteria. We compared the clinico-radiological characteristics of cerebral amyloid angiopathy-related intracerebral hemorrhage. We also investigated the detection rate of cerebral amyloid angiopathy with respect to the origins of the specimens. Pathological examination revealed that 22 subjects were positive for vascular amyloid. The number of the cerebral microbleeds located in the deep or infratentorial region was significantly larger in the negative group than in the positive group (P <.05). There was no significant difference in the distribution of lobar cerebral microbleeds and in the prevalence of hypertension. In the probable cerebral amyloid angiopathy-related intracerebral hemorrhage patients, the probability of having vascular amyloid detected by biopsy of both hematoma and parenchyma was 100%. Rebleeding in the postoperative periods was observed in 2 cases (9.1%) of the positive group. Our results demonstrate the importance and safety of biopsy simultaneously performed with hematoma evacuation. Deep or infratentorial microbleeds are less correlated with cerebral amyloid angiopathy-related intracerebral hemorrhage than with noncerebral amyloid angiopathy-related intracerebral hemorrhage.

Cerebral Amyloid Angiopathy-related Intracerebral Hemorrhage Score For Predicting Outcome

The existing intracerebral hemorrhage (ICH) scores were based on the clinical and anatomical parameters of all primary ICH. We aimed to study whether the original ICH Score can predict cerebral amyloid angiopathy (CAA)-related ICH mortality and functional outcome and whether modified score can improve the predictions. The patients with ICH were consecutively recruited from 21 tertiary and secondary hospitals across Mainland China from January 2012 to December 2014. CAA-related ICH was defined as Boston Criteria. Logistic regression was performed in the derivation cohort of patients with CAA-related ICH to identify predictors of 3-month mortality and good outcome [modified Rankin score (mRS) of 0-2 at 3 months]. The areas under the receiver operating characteristic curves (AUCs) were used to assess model discrimination. A total of 360 CAA-related ICH patients were included. According to AUCs, the original ICH Score was less reliable predictor for mortality (AUCs=0.69) and good outcome (AUCs=0.67) in CAA- related patients. The range of CAA-related ICH score values is 0 to 7. The scale consist of four clinical items and the score points were assigned based on the Glasgow Coma Scale score on admission, age, presence of intraventricular hemorrhage, and presence of midline shift. CAA-related ICH score showed good discrimination in the derivation cohort (AUCs: 0.87 for mortality; 0.80 for good clinical outcome) and validation cohort (AUCs: 0.89 for mortality; 0.81 for good clinical outcome). The original ICH Score may be less reliable in predicting mortality and good clinical outcome at 3 months for CAA-related ICH patients. The modified scores improve its ability to predict clinical outcome at 3 months for CAA-related ICH.

Abstract W P257: Predictors of the CT Angiography Spot Sign in Deep and Lobar Intracerebral Hemorrhage

Objectives: Intracerebral hemorrhage (ICH) patients with CT angiography (CTA) spot sign are at increased risk of hematoma expansion and poor outcome. Since ICH is often the acute manifestation of a chronic cerebral vasculopathy, we investigated whether different clinical or imaging characteristics predict spot sign presence in patients with different underlying vasculopathies. Using ICH location as a surrogate for hypertension-related ICH and cerebral amyloid angiopathy-related ICH, we identified risk factors associated with spot sign. METHODS: We retrospectively analyzed a prospective cohort of consecutive spontaneous ICH patients with available CTA. Spot sign presence was ascertained by two independent readers blinded to clinical data. We assessed potential predictors of spot sign be performing uni- and multivariable logistic regression, analyzing deep and lobar ICH separately. RESULTS: 649 patients were eligible, 291 (45%) deep and 358 (55%) lobar ICH. Median time from symptom onset to CTA was 4.5 (IQR 5.2) and 5.7 (IQR 7.4) hours in patients with deep and lobar ICH, respectively. At least one spot sign was present in 76 (26%) deep and 103 (29%) lobar ICH patients. In mutivariable logistic regression, independent predictors of spot sign in deep ICH were warfarin (OR 2.82 [95%CI 1.06-7.57]; p=0.03), time from symptom onset to CTA (OR 0.9 [95%CI 0.81-0.97]; p=0.02), and baseline ICH volume (OR 1.27 [95%CI 1.14-1.43]; p=2.5E-5; per 10 mL increase). Predictors of spot sign in lobar ICH were preexisting dementia (OR 2.7 [95%CI 1.15-6.43]; p=0.02), warfarin (OR 4.01 [95%CI 1.78-9.29]; p=0.009), and baseline ICH volume (OR 1.27 [95%CI 1.17-1.39]; p=5.4E-8; per 10 mL increase). As expected, spot sign presence was a strong predictor of hematoma expansion in both deep (OR 3.52 [95%CI 1.72-7.2]; p=0.0005) and lobar ICH (OR 6.53 [95%CI 3.23-13.44]; p=2.2E-7). CONCLUSIONS: The most potent associations with spot sign are shared by deep and lobar ICH, suggesting that ICH caused by different vasculopathic processes share biological features. The relationship between preexisting dementia and spot sign in lobar ICH, but not deep ICH, suggests that ICH occurring in the context of more advanced cerebral amyloid angiopathy may be more likely to have prolonged bleeding.

Left Ventricle Hypertrophy is Common in Patients with Cerebral Amyloid Angiopathy-Related Intracerebral Hemorrhage and Is Independently Associated with Long-Term Mortality.

Background: A post-hoc analysis of the PROGRESS trial suggested that long-term anti-hypertensive therapy prevents intracerebral hemorrhage (ICH) in patients with cerebral amyloid angiopathy (CAA). However, the burden of underlying hypertension in patients with CAA is unclear, and it is also unclear whether this hypertensive burden contributes to long-term outcome in survivors of CAA-related ICH. Left ventricle (LV) hypertrophy is a measure of the chronicity and severity of hypertension and could be used to assess hypertensive end-organ damage in patients with CAA. Objective: To test the hypothesis that LV hypertrophy is common in patients with CAA-related ICH and is associated with increased long-term mortality and shorter survival in those patients. Methods: This was a retrospective analysis of a prospectively collected cohort of consecutive patients with primary ICH presenting to a single academic center. We included patients presenting between January/2000 to December/2010, age &gt; 55 years, who received a transthoracic echocardiogram (echo) during follow-up and were diagnosed with definitive, probable or possible CAA according to the Boston criteria. LV mass index (10g/m2) was calculated according to Penn convention. Ninety-day survivors were followed prospectively for long-term mortality or censoring at January/2012. Cox proportional hazards models were used to identify predictors of mortality as time-dependent variables adjusting for potential confounders. Results: Among 211 patients who met inclusion criteria, the mean time to follow-up was 4.28 ± 2.7 years; the median time to echocardiogram was 3 days (IQR:49). The mean age was 75.7 ± 9.1 years; 103 (49%) were male. LV hypertrophy was present in 55 (31.8%) patients and 152 (72%) patients survived more than 90 days. In multivariate analysis, after adjusting for baseline characteristics, LV mass index (10g/m2) was associated with higher long-term mortality (HR: 1.20; 95%CI: 1.01-1.4; p=0.039). On Cox-regression, LV hypertrophy was independently associated with shorter long-term survival (HR 1.91; 95%CI 1.05-3.47; p=0.034). Conclusions: LV hypertrophy is common in patients with CAA-related ICH and is associated with increased risk of subsequent mortality among 90-day survivors.